Takaoka, Kensuke

Abstract Introduction: Patients with multiple myeloma (MM) have an increased risk of infection secondary to hypogammaglobulinemia, due to myeloma itself and anti-myeloma therapies. Prophylactic immunoglobulin (Ig) supplementation has been considered a potential strategy to reduce the risk of infections. A randomized controlled trial (Chapel, Lancet, 1994) demonstrated a reduction in both overall and major infections with the use of Ig. However, its real-world benefit remains unclear and prophylactic Ig is not routinely given as part of standard therapies. Furthermore, little is known regarding the routine use of Ig in the context of modern therapeutic agents such as chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibody therapies. To address this gap, we conducted an updated systematic review and meta-analysis (SRMA) to elucidate the efficacy of prophylactic immunoglobulin in patients with MM. Methods: We performed a SRMA of observational and randomized controlled trials comparing the outcomes in patients with MM who received prophylactic immunoglobulin versus those who did not. A comprehensive search of PubMed, Scopus, and Cochrane CENTRAL databases was conducted up to July 2025, along with a manual review of the reference lists from relevant articles. This review adheres to the recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. R software version 4.5.1 was used for statistical analyses. Results: A total of 18 studies were included in the systematic review. Among them, 11 studies compared patients who received immunoglobulin prophylaxis with those who did not (“Ig” versus “no Ig” groups). The remaining seven studies analyzed the same group of patients, comparing periods when they were receiving Ig (“on-Ig”) with periods when they were not (“off-Ig”). Among 18 studies, 13 studies were included in meta-analysis due to data availability (eight from the former group and five from the latter group). First, we conducted a meta-analysis of 1,234 patients from the eight studies that preceded this analysis, comparing Ig and no-Ig. Three studies included MM patients treated with bispecific antibodies, two focused on those treated with autologous stem cell transplantation (ASCT), and one on those treated with anti-CD38 antibodies. The dose of Ig was 0.4 g/kg every four weeks in most studies, and the timing of initiation of Ig varied across studies. The majority of Ig was delivered through an intravenous route. Most studies defined severe infections as those greater than grade 3 according to the Common Terminology Criteria for Adverse Events, while one study defined them as infections requiring intravenous or oral antibiotic treatment. The incidence of severe infection was significantly lower in patients who received prophylactic Ig compared with those who did not (odds ratio [OR] 0.22; 95% CI 0.08-0.63; p = 0.005). There was no significant difference in the overall infection rate between the two groups (OR 0.97; 95% CI 0.68-1.37; p = 0.85). A subgroup analysis by treatment type (chemotherapy, bispecific antibody, and ASCT) showed no significant differences in the overall infection rate among the subgroups (ASCT: OR 0.97; 95% CI 0.64-1.45; Bispecific antibody: OR 0.74; 95% CI 0.49-1.11). However, a significant reduction in the rate of severe infections was observed in patients treated with bispecific antibodies (OR 0.33; 95% CI 0.13-0.85; p = 0.021). Next, we analyzed 460 patients from the latter five studies comparing on-Ig and off-Ig. The incidence rate ratio (IRR) of overall infection was significantly lower during on-Ig periods compared with off-Ig periods (IRR 0.62; 95% CI 0.43-0.88; p = 0.0082). Conclusions: In patients with MM, prophylactic Ig use was associated with a low incidence of severe infections. Furthermore, the incidence rate ratio of overall infection was lower during periods of Ig prophylaxis compared to periods without Ig. These findings underscore the potential efficacy of a routine Ig prophylaxis in patients with MM to mitigate the risk of infections. Since this meta-analysis does not include studies involving patients treated with CAR-T therapy, further studies are warranted to evaluate the effectiveness of Ig in patients receiving novel therapies such as CAR-T therapy, while also considering the cost and time associated with Ig administration in real-world clinical practice.

Abstract Introduction: The epidemiology and clinical characteristics of familial myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) remain poorly understood, particularly among Native Hawaiians and Other Pacific Islanders (NHOPI). Methods: To investigate the real-world evidence in this area, we conducted a retrospective study at the Queen's Medical Center (QMC), Hawaii's largest tertiary referral hospital. The data was gathered from QMC's electronic medical record. Familial MDS or familial AML patients in this study were defined as MDS or AML occurring in a patient with a family history of MDS and/or AML. Patients with acute promyelocytic leukemia (APL), as well as those with a family history of APL, were excluded given the differences in disease characteristics and its genetic phenotype from other AML subtypes. Unspecified leukemia was defined when a patient had a family history of leukemia but the specific subtype was unavailable. Some patients underwent comprehensive panel testing, while others had targeted next-generation sequencing (NGS) assays ordered at the discretion of their treating physicians. NGS was performed at Clinical Laboratory Improvement Amendments (CLIA)-certified commercial laboratories. NGS panels typically included the following genes: ASXL1, BCOR, BRAF, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, PDGFRA, PHF6, PML, PTPN11, RUNX1, SETBP1, STAG2, TET2, TP53, and WT1. Results: Among 1,686 MDS/AML patients presented between January 2012 and July 2023, 12 (0.71 %) had familial MDS/AML and 25 (1.48%) had a family history of unspecified leukemia. While no NHOPI were identified among familial MDS/AML cases, 20% of patients with a family history of unspecified leukemia were NHOPI. The median age at diagnosis of familial MDS/AML was 70 years, and 50% of familial MDS patients had MDS with low blasts based on the World Health Organization 2022 classification. Based on International Consensus Classification 2022 criteria, 25% had MDS, not otherwise specified (NOS) with multilineage dysplasia, and 25% had MDS, NOS with single lineage dysplasia. Among the eight patients with familial MDS, the median overall survival (OS) was 12.7 years, with an estimated 5-year OS rate of 75.0% (95% CI: 12.8–96.1), based on Kaplan–Meier analysis. In contrast, the three patients with familial AML had a median survival of 10.2 months and a 3-year OS estimate of 33.3% (95% CI: 0.90–77.4). For patients with a family history of unspecified leukemia, the median survival was not reached during the follow-up period. The estimated 5-year OS rate was 53.3% (95% CI: 12.5–82.7) for the 10 familial MDS cases and 53.3% (95% CI: 20.9–77.3) for the 13 familial AML cases. When combining all familial cases, the median OS for familial MDS (n = 18) was 12.7 years with a 5-year OS rate of 61.9% (95% CI: 26.8–84.0). The median OS for familial AML (n = 16) was 0.90 years, and the estimated 5-year OS rate was 48.2% (95% CI: 20.8–71.3). When all cases were combined, there was no statistically significant difference in overall survival between patients with familial AML (n = 16) and those with familial MDS (n = 18), based on the log-rank test (p = 0.22). Regarding NGS, ASXL1 mutations were the most frequent in the cohort, detected in six of the 32 NGS tests performed (18.8%). Among patients with familial MDS, recurrent somatic mutations were observed in several genes. ASXL1 mutations were identified in two patients; one had a brother with MDS, and the other had a maternal uncle with unspecified leukemia. DNMT3A mutations were also found in two patients with familial MDS; one had a brother with MDS, and the other had a paternal uncle with MDS. SRSF2 mutations were detected in two patients; one had a brother with MDS, and the other had a granddaughter with leukemia. Additionally, SF3B1 mutations were found in two patients; one had a mother with MDS, and the other had a paternal uncle with MDS. Two patients with familial AML were found to have ASXL1 mutation, both with fathers who had unspecified leukemia. Otherwise, no other repeated mutations were found. None of the cases involved NHOPI patients. Conclusion: Our study offers new insights into familial MDS/AML within Hawaii's multiethnic population. Although no NHOPI patients were identified among the familial cases, our findings underscore the genetic heterogeneity and clinical variability of these disorders.